Caspase-1 inhibition by VX-765 administered at reperfusion in P2Y(12) receptor antagonist-treated rats provides long-term reduction in myocardial infarct size and preservation of ventricular function.
Caspase-1 inhibition by VX-765 administered at reperfusion in P2Y(12) receptor antagonist-treated rats provides long-term reduction in myocardial infarct size and preservation of ventricular function.
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在P2Y（12）受体拮抗剂治疗的大鼠中施用的VX-765抑制CASPase-1抑制caspase-1，可长期降低心肌梗塞大小和心室功能的保存。
DOI：
10.1007/s00395-018-0692-z
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发表时间：
2018-07-10
影响因子：
9.5
通讯作者：
Alvarez DF
中科院分区：
文献类型：
--
作者：
Audia JP;Yang XM;Crockett ES;Housley N;Haq EU;O'Donnell K;Cohen MV;Downey JM;Alvarez DF
急性心肌梗死患者在再灌注前接受P2 Y β 12受体拮抗剂，这种治疗降低了死亡率或心力衰竭，但没有消除。我们测试了在再灌注时给予的半胱天冬酶-1抑制剂VX-765（临床使用的要求）是否可以在已用P2 Y β 12受体拮抗剂治疗的缺血/再灌注临床前模型中持续减少梗死和长期保存心室功能。为了解决这一假设，开胸大鼠进行60分钟左冠状动脉分支闭塞/120分钟再灌注。在再灌注之前立即静脉内施用媒介物或抑制剂。仅使用车辆时，60.3 ± 3.8%的风险区出现梗死。替格瑞洛（一种P2 Y β 12拮抗剂）和VX-765分别将梗死面积减少至42.8 ± 3.3%和29.2 ± 4.9%。替格瑞洛与VX-765组合进一步将梗死降低至17.5 ± 2.3%。与最近的临床试验类似，替格瑞洛和缺血后处理联合使用并没有产生额外的心脏保护作用。VX-765加另一种P2 Y12拮抗剂坎格雷洛也减少了梗死，并在再灌注增加至3天时保留了心室功能。此外，VX-765减少了无血离体大鼠心脏中的梗死，表明至少一部分有害的半胱天冬酶-1活化起源于心脏组织。虽然前药VX-765仅在缺血前开始时保护离体心脏，但其活性衍生物VRT-043198在再灌注时开始时提供相同量的保护，表明即使在无血心脏中，胱天蛋白酶-1似乎仅在再灌注时发挥其损伤。此外，VX- 765降低循环IL-1，防止心脏糖酵解酶的损失，保护线粒体复合物I活性，并减少乳酸脱氢酶（焦亡的标志物）的释放。我们的研究结果是首次证明了临床级药物在再灌注时提供额外的，持续的梗死面积减少时，加入P2 Y β 12受体拮抗剂。
Patients with acute myocardial infarction receive a P2Y12 receptor antagonist prior to reperfusion, a treatment that has reduced, but not eliminated, mortality, or heart failure. We tested whether the caspase −1 inhibitor VX-765 given at reperfusion (a requirement for clinical use) can provide sustained reduction of infarction and long- term preservation of ventricular function in a pre-clinical model of ischemia/reperfusion that had been treated with a P2Y12 receptor antagonist. To address, the hypothesis open-chest rats were subjected to 60-min left coronary artery branch occlusion/120-min reperfusion. Vehicle or inhibitors were administered intravenously immediately before reperfusion. With vehicle only, 60.3 ± 3.8% of the risk zone suffered infarction. Ticagrelor, a P2Y12 antagonist, and VX-765 decreased infarct size to 42.8 ± 3.3 and 29.2 ± 4.9%, respectively. Combining ticagrelor with VX-765 further decreased infarction to 17.5 ± 2.3%. Similar to recent clinical trials, combining ticagrelor and ischemic postconditioning did not result in additional cardioprotection. VX-765 plus another P2Y12 antagonist, cangrelor, also decreased infarction and preserved ventricular function when reperfusion was increased to 3 days. In addition, VX-765 reduced infarction in blood-free, isolated rat hearts indicating at least a portion of injurious caspase-1 activation originates in cardiac tissue. While the prodrug VX-765 only protected isolated hearts when started prior to ischemia, its active derivative VRT-043198 provided the same amount of protection when started at reperfusion, indicating that even in blood-free hearts, caspase- 1 appears to exert its injury only at reperfusion. Moreover, VX- 765 decreased circulating IL-1, prevented loss of cardiac glycolytic enzymes, preserved mitochondrial complex I activity, and decreased release of lactate dehydrogenase, a marker of pyroptosis. Our results are the first demonstration of a clinical-grade drug given at reperfusion providing additional, sustained infarct size reduction when added to a P2Y12 receptor antagonist.
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影响因子：
16
作者：
Martinon, F;Burns, K;Tschopp, J
通讯作者：
Tschopp, J
影响因子：
5
作者：
Holly, TA;Drincic, A;Cryns, VL
通讯作者：
Cryns, VL
影响因子：
3.7
作者：
Audia JP;Lindsey AS;Housley NA;Ochoa CR;Zhou C;Toba M;Oka M;Annamdevula NS;Fitzgerald MS;Frank DW;Alvarez DF
通讯作者：
Alvarez DF
影响因子：
8.7
作者：
Man SM;Kanneganti TD
通讯作者：
Kanneganti TD
影响因子：
64.8
作者：
Chouchani, Edward T.;Pell, Victoria R.;Gaude, Edoardo;Aksentijevic, Dunja;Sundier, Stephanie Y.;Robb, Ellen L.;Logan, Angela;Nadtochiy, Sergiy M.;Ord, Emily N. J.;Smith, Anthony C.;Eyassu, Filmon;Shirley, Rachel;Hu, Chou-Hui;Dare, Anna J.;James, Andrew M.;Rogatti, Sebastian;Hartley, Richard C.;Eaton, Simon;Costa, Ana S. H.;Brookes, Paul S.;Davidson, Sean M.;Duchen, Michael R.;Saeb-Parsy, Kourosh;Shattock, Michael J.;Robinson, Alan J.;Work, Lorraine M.;Frezza, Christian;Krieg, Thomas;Murphy, Michael P.
通讯作者：
Murphy, Michael P.